Ortho-Tri-Cyclen Lo

"If you do not want to get pregnant, there are many birth control
options to choose from. No one product is best for everyone. The only sure way
to avoid pregnancy and sexually transmitted infections (STIs or STDs) is not to
have any sexual"...

Ortho-Tri-Cyclen Lo

CLINICAL PHARMACOLOGY

Oral Contraception

Combination oral contraceptives act by suppression of gonadotropins. Although
the primary mechanism of this action is inhibition of ovulation, other alterations
include changes in the cervical mucus (which increase the difficulty of sperm
entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor binding studies, as well as studies in animals and humans, have shown
that norgestimate and 17-deacetyl norgestimate, the major serum metabolite,
combine high progestational activity with minimal intrinsic androgenicity.90-93
Norgestimate, in combination with ethinyl estradiol, does not counteract the
estrogen-induced increases in sex hormone binding globulin (SHBG), resulting
in lower serum testosterone.90,91,94

Pharmacokinetics

Absorption

Norgestimate (NGM) and ethinyl estradiol (EE) are rapidly absorbed following
oral administration. Norgestimate is rapidly and completely metabolized by first-pass
(intestinal and/or hepatic) mechanisms to norelgestromin (NGMN) and norgestrel
(NG), which are the major active metabolites of norgestimate. Mean pharmacokinetic
parameters for NGMN, NG and EE during three cycles of administration of ORTHO
TRI-CYCLEN® Lo are summarized in Table 1. These results indicate that: (1)
Peak serum concentrations of NGMN and EE were generally reached by 2 hours after
dosing; (2) Accumulation following multiple dosing of the 180 µg NGM / 25 µg
dose is approximately 1.5 to 2 fold for NGMN and approximately 1.5 fold for
EE compared with single dose administration, in agreement with that predicted
based on linear kinetics of NGMN and EE; (3) The kinetics of NGMN are dose proportional
following NGM doses of 180 to 250 µg; (4) Steady-state conditions for NGMN following
each NGM dose and for EE were achieved during the three cycle study; (5) Non-linear
accumulation (4.5-14.5 fold) of norgestrel was observed as a result of high
affinity binding to SHBG, which limits its biological activity.100
The effect of food on the pharmacokinetics of ORTHO TRI-CYCLEN® Lo has not
been studied. Table 1 provides a summary of norelgestromin, norgestrel and ethinyl
estradiol pharmacokinetic parameters.

Distribution

Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG. Ethinyl estradiol is extensively bound (> 97%) to serum albumin.

Metabolism

Norgestimate is extensively metabolized by first-pass mechanisms in the gastrointestinal tract and/or liver. Norgestimate's primary active metabolite is norelgestromin. Subsequent hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is also active and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Special Populations

Effects of Body Weight, Body Surface Area, and Age

The effects of body weight, body surface area, age and race on the pharmacokinetics
of norelgestromin, norgestrel and ethinyl estradiol were evaluated in 79 healthy
women using pooled data following single dose administration of NGM 180 or 250
µg / EE 25 µg tablets in four pharmacokinetic studies. Increasing body weight
and body surface area were each associated with decreases in Cmax and AUC0-24h
values for norelgestromin and ethinyl estradiol and increases in CL/F (oral
clearance) for ethinyl estradiol. Increasing body weight by 10 kg is predicted
to reduce the following parameters: NGMN Cmax by 9% and AUC0-24h
by 19%, norgestrel Cmax by 12% and AUC0-24h by 46%, EE Cmax by 13%
and AUC0-24h by 12%. These changes were statistically significant.
Increasing age was associated with slight decreases (6% with increasing age
by 5 years) in Cmax and AUC0-24h for norelgestromin and were statistically
significant, but there was no significant effect for norgestrel or ethinyl estradiol.
Only a small to moderate fraction (5-40%) of the overall variability in the
pharmacokinetics of norelgestromin and ethinyl estradiol following ORTHO TRI-CYCLEN®
Lo Tablets may be explained by any or all of the above demographic parameters.

In clinical studies involving 1673 subjects with a mean weight of 141 pounds, there was no association between pregnancy and weight.

Renal and Hepatic Impairment

No studies with ORTHO TRI-CYCLEN® Lo have been conducted in women with renal or hepatic impairment.

Drug-Drug Interactions

Although norelgestromin and its metabolites inhibit a variety of P450 enzymes
in human liver microsomes, under the recommended dosing regimen, the in vivo
concentrations of norelgestromin and its metabolites, even at the peak serum
levels, are relatively low compared to the inhibitory constant (Ki). Interactions
between oral contraceptives and other drugs have been reported in the literature.
No formal drug-drug interaction studies were conducted with ORTHO TRI-CYCLEN®
Lo (see PRECAUTIONS).